I’ve been asked to give a talk on our recent research on how cancer cells metastasise, that is, how cells in a primary tumour leave the primary tumour and spread and form new tumour colonies in distant sites throughout the body, that is the process of metastasis. This is more than just an academic issue since metastases are responsible for about 90% of the deaths associated with cancer.
What research are you presenting?
Much of the research in my laboratory focusses on how carcinoma cells, which constitute about 80% of clinical cancer, undergo a profound change in their biology where they change from an epithelial state, which is characteristic of the normal tissues from which these carcinomas originated, into a different state, a mesenchymal state, a connective tissue state. This profound change in their biology imparts to the carcinoma cells the ability to invade nearby tissues, to enter into the blood stream, to spread to distant sites and there even to begin to initiate the formation of new colonies of tumour cells, that is new metastases.
What are the most exciting elements of the work you’ve been doing?
One quite striking discovery that we made some years ago was that if one forces cells from an epithelial to mesenchymal state one of the by-products of that conversion is that often cancer cells enter into a state called the cancer stem cell state. Cancer stem cells are cells that have acquired the ability to seed new tumours. It turns out that most of the cells in a tumour, if you take them out of the tumour and put them in a mouse, will fail to seed a new tumour. But a minority of cells, the so-called cancer stem cells, have tumour initiating, tumour seeding ability and thus are able to seed new tumours when they’re implanted in a mouse. Such cells are also able to serve as the founders of new metastatic colonies, should they spread to distant tissues in the mouse.
Can we now target these stem cells?
We’ve only begun to learn how to target these cancer stem cells, which indeed are quite dangerous because they exhibit an elevated resistance to most existing forms of therapy. As a consequence, research in a number of laboratories has begun to attempt to develop drugs that specifically target the cancer stem cells, the minority of cells in tumours, rather than the majority of non-stem cells in the tumours which are more responsive, more sensitive to killing by existing chemotherapeutics or radiotherapy.
What are some of the other points that you will be highlighting in your talk?
In addition to the description of how cancer cells spread, I will also be describing the fact that we’ve begun to understand why certain breast cancers become aggressive and others don’t. This turns out to reflect the fact that certain cancer stem cells have the proclivity, the ability to spontaneously go from a benign epithelial state into an aggressive mesenchymal state whereas other cancer stem cells lack that ability. As a consequence, for example, luminal cancers of the breast lack the ability to generate new cancer stem cells whereas basal carcinomas of the breast, which are quite nasty often, readily generate or spawn new cancer stem cells which, as I’ve said before, can be quite dangerous.
How can this be clinically applied?
The work that I’ve described is still far away from actual clinical translation. Some might say, “Well, if you can’t translate it into clinical application then why do it?” But the fact of the matter is that the research of this sort is discovering that part of the reason that existing clinical therapies have failed is attributable to the existence of these cancer stem cells whose existence was only realised over the last five, six, seven years and which represent a hidden enemy that now has come into light and now represents an obvious and highly attractive target for therapy. That doesn’t mean that, in fact, this will be immediately translatable. I was involved in discovering a protein in 1981 which 25 years later became useful in treating breast cancer, that is through the antibody Herceptin. So the discovery of some basic, fundamental attributes of cancer cells is not instantaneously translatable into clinical applications.
What’s the take home message?
The take home message from my talk will be that there’s far more to determining the behaviour of cancer cells, and thus tumours, than the sequencing of their DNA because these conversions of cells from a non-cancer stem cell state to a cancer stem cell state don’t involve changes in the sequence of DNA molecules but rather a re-wiring of the signalling circuitry within the cancer cells that does not involve shifts in the structure of the DNA. Currently there is much interest in focus on sequencing the genomes of cancer cells but it’s my conviction that such sequencing efforts reveal only part of the aberrant behaviour of cancer cells. One will need to study these non-DNA based changes in cells which will, in turn, require an entirely new technology in terms of evaluating the data, that is a new form of bioinformatics, to be able to integrate information on how cancer cells DNA and mutations in the DNA and the non-genetic, non-DNA based changes in cells conspire with one another to generate the final aggressive state of many carcinoma cells.